Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.
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Authors
Lloyd, MG
Huckvale, R
Cheung, K-MJ
Rodrigues, MJ
Collie, GW
Pierrat, OA
Gatti Iou, M
Carter, M
Davis, OA
McAndrew, PC
Gunnell, E
Le Bihan, Y-V
Talbot, R
Henley, AT
Johnson, LD
Hayes, A
Bright, MD
Raynaud, FI
Meniconi, M
Burke, R
van Montfort, RLM
Rossanese, OW
Bellenie, BR
Hoelder, S
Huckvale, R
Cheung, K-MJ
Rodrigues, MJ
Collie, GW
Pierrat, OA
Gatti Iou, M
Carter, M
Davis, OA
McAndrew, PC
Gunnell, E
Le Bihan, Y-V
Talbot, R
Henley, AT
Johnson, LD
Hayes, A
Bright, MD
Raynaud, FI
Meniconi, M
Burke, R
van Montfort, RLM
Rossanese, OW
Bellenie, BR
Hoelder, S
Document Type
Journal Article
Date
2021-12-09
Date Accepted
2021-11-30
Abstract
We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.
Citation
Journal of medicinal chemistry, 2021, 64 (23), pp. 17079 - 17097
Source Title
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
1520-4804
1520-4804
Collections
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 4 (including Analytical Chemistry)
Target Evaluation and Molecular Therapeutics
Hit Discovery & Structural Design
Medicinal Chemistry 4 (including Analytical Chemistry)
Target Evaluation and Molecular Therapeutics
Hit Discovery & Structural Design